The invention pertains to medical methods, compounds and devices and, particularly, to the treatment of abnormal uterine bleeding and to improved female contraception.
A common cause of abnormal uterine bleeding is the presence of leiomyomas, or fibroids, in the uterus. The mechanism by which these neoplasms cause abnormal bleeding is not known, but there are several hypotheses. One is that leiomyomas may increase the surface area of the endometrial cavity. Another is that these neoplasms cause changes in the venous structures in the endometrium and myometrium by compressing veins which results in venule ectasia. Abnormal uterine bleeding is also associated with the occurrence of endometrial polyps, adenomyosis, perimenopausal hormonal transition, as well as idiopathic bleeding (i.e., bleeding for which there is no obvious cause). Furthermore, abnormal uterine bleeding often results from the use of progestin-only contraceptives.
Current therapies for abnormal uterine bleeding are limited. Surgical therapies include hysterectomies, myomectomies, and endometrial ablation. These therapies require anaesthesia and can result in significant morbidity and, rarely, mortality. According to a study by Wilcox et al, based on figures from 1988-1989, approximately forty percent (40%) of the 1.7 million women who have had hysterectomies each year in the United States have a diagnosis related to abnormal uterine bleeding.
Current non-surgical therapies for abnormal uterine bleeding focus on the manipulation of the steroid hormone environment, including, use of oral contraceptives, GnRH agonists and antagonists, and progestins. These therapies result in limited efficacy and/or a significant impact on other steroid hormone-dependent tissues, including breast or bone.
Accordingly, an object of this invention is to provide improved methods for medical therapy and, more particularly, improved methods for treating abnormal uterine bleeding.
More particularly, an object of this invention is to provide improved methods for treating abnormal uterine bleeding that are non-surgical and that do not have detrimental side effects on other bodily tissues, such as, bone, cardiovascular function and breast tissue.
A further object of the invention is to provide such methods as can be effected using known compounds that are already approved for clinical use in humans.
Still another object is to provide such methods as can be applied locally to the uterus and that are reversible.
Yet another object of the invention is to provide improved methods, compounds and devices for female contraception.
A further object of this invention is to provide improved devices and agents for treating abnormal uterine bleeding that are minimally invasive.
A still further object of the invention is to provide such apparatus and agents that can be deployed by the patient, without assistance from a health care professional.
Yet another object is to provide systems for non-surgical treatment of abnormal uterine bleeding that utilize low-cost delivery technologies.
The foregoing objects are among those met by the invention which provides, in one aspect, medical methods for treating abnormal uterine bleeding via application of compounds that block uterine epithelial, stromal or leiomyoma cell response to angiogenic growth factors by interfering with the growth factors themselves, by blocking receptors in the uterine epithelial or stromal cells to those growth factors, and/or by inhibiting other receptors to those growth factors. For sake of convenience, uterine epithelial, stromal and leiomyoma cells are collectively and individually referred to throughout this document as uterine stromal cells).
The compounds include interferons, particularly type I interferons, pirfenidone, heparin, heparin-like polyaromatic anionic compounds, heparin-sulfate-based compounds, secreted or soluble FGF receptors, and/or RGD-peptide. The angiogenic growth factors to which response is blocked, and their receptors, include basic fibroblast growth factor (bFGF), FGF receptors (FGFR), e.g., FGF receptor 1 (FGFR 1) and FGF receptor 2 (FGFR 2), acidic fibroblast growth factor (aFGF), transforming growth factor xcex2 (TGF-xcex2), platelet-derived growth factor (PDGF), heparin binding epidermal growth factor (HBEGF), vascular endothelial growth factor (VEGF), parathyroid hormone-related protein (PTHrP) and/or prolactin.
The methods contemplate introducing the aforementioned response-blocking compounds into the body of a patient either systemically, e.g., via injection or implant, or locally to the uterus, e.g., via medicated intrauterine devices, foams and the like.
In related aspects, the invention provides improved formulations for treatment of abnormal uterine bleeding. These comprise the aforementioned response-blocking compounds in solutions, gels, foams or other biologically compatible bases, that release the compounds immediately or via time-release into the patient""s body. The formulations can be used for systemic or local treatment.
In still other related aspects, the invention provides devices for treatment of abnormal uterine bleeding. These include interuterine devices (IUD""s), intravaginal devices (IVD""s), cervical caps, diaphragms, intravaginal creams or foams, and/or intravaginal dissolving capsules containing the aforementioned response-blocking compounds.
Other aspects of the invention provide improved female contraceptive methods that reduce the likelihood of conception while, at the same, avoiding the heretofore common side effect of uterine bleeding. The methods contemplate introducing into a patient a progestin-based, and preferably progestin-only, contraceptive substance, and an angiogenic growth factor receptor blocker (e.g., interferon, pirfenidone, heparin, heparin-like polyaromatic anionic compounds, heparin-sulfate-based compounds, secreted or soluble FGF receptors, and/or RGD-peptide) as described above. These contraceptive substance and response-blocking compounds, which can be administered at differing times or concomitantly with one another, are introduced into the patient systemically or locally.
Further aspects of the invention provide contraceptive formulations, and apparatus for delivering the same, comprising the progestin-based contraceptive substances and responseblocking compounds, as discussed above.
These and other aspects of the invention are evident in the attached drawings and in the description that follows.